Human psychopharmacological research with hallucinogenic drugs has lagged behind basic neuropharmacology, thus preventing the necessary interface between human and animal work. Hallucinogenic drugs continued being abused, particularly by young adults; there has been a rise in use over the last several years. This project will continue the human research on tryptamine hallucinogens made possible by a previous National Institute on Drug Abuse (NIDA) Small Grant: Human Psychopharmacology and Neuroendocrinology of DMT. The mechanisms by which N,N- dimethyltryptamine (DMT), an endogenous tryptamine hallucinogen and Schedule I drug of abuse, exerts its biological and psychological effects will be further characterized. A systematic human study of the biological and psychological effects of 4-phosphoryloxy-N,N- dimethyltryptamine (psilocybin), a longer acting Schedule I tryptamine hallucinogen which is more widely abused, also will be initiated. Specifically, five studies will be performed over the four years of support requested in this application. Ten to 12 subjects, all experienced hallucinogen users who are otherwise medically and psychiatrically healthy, will be recruited for each study. Recent advances in basic neuropharmacology concerning hallucinogenic drugs' effects and mechanisms of action will be applied, by attempting to modify DMT's biological and psychological effects with selective blockade of serotonin (5-HT) receptors, in particular, the 5-HT1A and 5-HT2 subtypes. An attempt will be made to develop tolerance to the acute effects of DMT in humans, something that has never been demonstrated. It will be determined if menstrual phase affects the response to DMT in women. Finally, a dose/concentration-response study of psilocybin's neuroendocrine, cardiovascular, autonomic and psychological effects in humans will be undertaken.